Atovaquone, chemical name being trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone, is a hydroxy-1,4-naphtoquinone, an analog of ubiquinone, with antipneumocystic activity. Atovaquone is potently active (in animals and in vitro) against Pneumocystis carinii, Plasmodia, and tachyzoite and cyst forms of Toxoplasma gondii. Due to its inhibitory effect in sensitive parasites, atovaquone can act by selectively affecting mitochondrial electron transport and parallel processes such as ATP and pyrimidine biosynthesis, thus has got great pharmaceutical interest/importance. Atovaquone is the trans-isomer of 2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone whose synthesis, activity and uses are disclosed in the patent Nos. U.S. Pat. No. 5,053,432 ('432 patent) and EP0362996.
There are only a few reports available for the preparation of atovaquone exploring various synthetic alternative. Those report are mainly based on a decarboxylative condensation process, as shown in scheme 1, which is analogous to the method disclosed by Fieser (J. American Chemical Society, vol. 70, 3174-3180 (1948)) yielding the condensation product at only about 1 to 6%. As reported, the production yield of atovaquone using process of the '432 patent is very poor, practically in the range of 3-5%.
Thus a search for a manufacturing process for the preparation of Atovaquone resulting in a satisfactory yield/purity of the final product remains undoubtedly of interest.
Apart from this, there is a great challenge in obtaining atovaquone having improved solubility and dissolution characteristics. However, there is only a single publication on the production of different crystalline forms of atovaquone, as disclosed in WO2006008752 ('752 publication). The '752 publication discloses that atovaquone can exist in three different polymorphic forms (designated as Form I, Form II and Form III) and provides analytical characterization for those polymorphs. The product obtained by the basic molecule patent was characterized for the first time in this publication, and designated as Form I. The stability data of the reported forms are not reported. However, it is important to note the reports on micro-particles of atovaquone, for example U.S. Pat. Nos. 6,018,080 and 6,649,659, disclose such micro-particles and processes for producing the same. These patents clearly disclose that the product manufactured by the process of the '432 patent, meaning the crystalline Form I, has poor bioavailability. Microparticles of atovaquone, prepared by a complicated process, have been described to have increased bioavailability. It has been disclosed that the process of U.S. Pat. No. 5,053,432 yields macroparticles of atovaquone that are not suitable to be administered as such, or even by conventional milling, due to poor solubility of the crystals in common organic/aqueous solvents. Therefore, there is a need in the art for new forms of atovaquone, which have improved solubility and bioavailability for making suitable pharmaceutical dosage forms.
Therefore the object of this invention is to develop alternative processes for the synthesis of atovaquone, more specifically in its trans isomer form with improved physical properties.